The acute effects of ethanol are mediated by binding to specific sites on proteins. We propose to elucidate the actions of ethanol on the GABAa and glycine receptors, two critical molecular targets for ethanol, by combining molecular, electrophysiological and behavioral methods.
Aim 1 will elucidate the specific location and orientation of the amino acids that form the ethanol binding site in heteromeric GABAa receptors. Our ongoing studies of glycine receptors suggest that zinc, a physiological modulator of glycine receptors, is important for ethanol action on these receptors, and Aim 1 will also define the molecular basis of this interaction.
In Aim 2, we will use GABAa and glycine receptor knockout and knockin mice to specify the behavioral effects of ethanol that are due to actions on these receptors.
Aim 3 will evaluate the neuronal consequences of receptor mutation. This will be accomplished by genomic analysis of key brain regions and by electrophysiological study of the mesolimbic reward pathway.
Aim 3 will also define effects of chronic ethanol consumption on global gene expression changes in the ventral tegmental area and nucleus accumbens, the two key areas of the mesolimbic pathway. These studies will use wild type mice and mice with GABAa or glycine receptors that are engineered to be insensitive to ethanol action. This novel approach will allow us to link changes in gene expression (and behavior, Aim 2) to alcohol actions on specific receptors. The long-range goal of this work is to define key protein sites that can serve as targets for new therapies to alleviate alcohol reinforcement, dependence an relapse.
Even though alcohol (ethanol) has been consumed for thousands of years, we know remarkably little about the way it produces its effects on the brain. An important advance was the identification of specific proteins (neurotransmitter receptors and ion channels) involved in communication between neurons as a target for ethanol. We will define how ethanol acts on these proteins using different techniques, ranging from the molecular to the behavioral level, using mutations in mice and other new technologies, with the final objective of defining key protein sites that can serve as targets for new therapies to alleviate alcohol addiction.
|Howard, Rebecca J; Trudell, James R; Harris, R Adron (2014) Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics. Pharmacol Rev 66:396-412|
|Borghese, Cecilia M; Hicks, Jessica A; Lapid, Daniel J et al. (2014) GABA(A) receptor transmembrane amino acids are critical for alcohol action: disulfide cross-linking and alkyl methanethiosulfonate labeling reveal relative location of binding sites. J Neurochem 128:363-75|
|Blednov, Yuri A; Benavidez, Jillian M; Black, Mendy et al. (2014) GABAA receptors containing ?1 subunits contribute to in vivo effects of ethanol in mice. PLoS One 9:e85525|
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|Trudell, James R; Messing, Robert O; Mayfield, Jody et al. (2014) Alcohol dependence: molecular and behavioral evidence. Trends Pharmacol Sci 35:317-23|
|Heusser, Stephanie A; Howard, Rebecca J; Borghese, Cecilia M et al. (2013) Functional validation of virtual screening for novel agents with general anesthetic action at ligand-gated ion channels. Mol Pharmacol 84:670-8|
|Ozburn, Angela Renee; Harris, R Adron; Blednov, Yuri A (2013) Chronic voluntary alcohol consumption results in tolerance to sedative/hypnotic and hypothermic effects of alcohol in hybrid mice. Pharmacol Biochem Behav 104:33-9|
|Blednov, Y A; Benavidez, J M; Black, M et al. (2013) Linking GABA(A) receptor subunits to alcohol-induced conditioned taste aversion and recovery from acute alcohol intoxication. Neuropharmacology 67:46-56|
|McCracken, Lindsay M; Blednov, Yuri A; Trudell, James R et al. (2013) Mutation of a zinc-binding residue in the glycine receptor *1 subunit changes ethanol sensitivity in vitro and alcohol consumption in vivo. J Pharmacol Exp Ther 344:489-500|
|Sauguet, Ludovic; Howard, Rebecca J; Malherbe, Laurie et al. (2013) Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel. Nat Commun 4:1697|
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